TTM2: Targeted Temperature Management after Cardiac Arrest (2021)

“In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death at 6 months than targeted normothermia.”

— The TTM2 Trial Investigators

1. Publication Details

  • Trial Title: Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.
  • Citation: Dankiewicz J, Cronberg T, Lilja G, et al; for the TTM2 Trial Investigators. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021;384(24):2283-2294. doi:10.1056/NEJMoa2100591.
  • Published: June 17, 2021, in The New England Journal of Medicine.
  • Author: Josef Dankiewicz, M.D., Ph.D.
  • Funding: Swedish Research Council, the European Union, and others.

2. Keywords

Cardiac Arrest, Out-of-Hospital Cardiac Arrest, Targeted Temperature Management, Therapeutic Hypothermia, Normothermia, Anoxic Brain Injury, Coma.

3. The Clinical Question

In adult patients who are comatose after an out-of-hospital cardiac arrest of presumed cardiac or unknown cause (Population), does targeted hypothermia at 33°C (Intervention) compared to targeted normothermia with early treatment of fever (Comparison) reduce all-cause mortality at 6 months (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Early trials suggested a benefit from therapeutic hypothermia (32-34°C) after cardiac arrest. However, the larger TTM trial (2013) showed no difference between targeting 33°C and 36°C, raising the crucial question of whether the benefit was from hypothermia itself or simply from the prevention of fever.
  • Knowledge Gap: It was unknown if targeted hypothermia was superior to a strategy of targeted normothermia (i.e., actively preventing and treating fever). A large, definitive trial was needed to clarify if inducing hypothermia was necessary.
  • Proposed Hypothesis: The authors hypothesized that targeted hypothermia at 33°C would decrease the risk of death at 6 months as compared with targeted normothermia.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, open-label, randomized, controlled trial with blinded outcome assessment.
  • Setting: 61 intensive care units (ICUs) in 14 countries.
  • Trial Period: Enrollment from November 2017 to January 2020.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who remained unconscious (GCS <8) after an out-of-hospital cardiac arrest of presumed cardiac or unknown cause, after return of spontaneous circulation (ROSC).
    • Exclusion Criteria: Unwitnessed arrest with asystole, time from ROSC to screening >180 minutes, or severe hemodynamic instability.
  • Intervention: Targeted hypothermia. Patients were cooled to and maintained at 33°C for 28 hours, followed by controlled rewarming and maintenance of a temperature of <37.8°C.
  • Control: Targeted normothermia. Patients were maintained at a temperature of ≤37.5°C. If the temperature rose to ≥37.8°C, cooling was initiated to bring it below this threshold.
  • Management Common to Both Groups: All patients received standardized, protocolized critical care, including sedation and prognostication guidelines.
  • Power and Sample Size: The trial was powered to detect a 7.5 percentage point difference in 6-month mortality, requiring 1900 patients.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 6 months.
    • Secondary Outcomes: Functional outcome at 6 months, assessed with the modified Rankin Scale (mRS).

6. Key Results

  • Enrollment and Baseline: 1850 patients were included in the final analysis (925 in the hypothermia group, 925 in the normothermia group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 6-month mortality. 465 of 925 patients (50.3%) in the hypothermia group died, compared with 446 of 925 patients (48.2%) in the normothermia group.
  • Secondary Outcomes: There was no significant difference in the proportion of patients with a poor functional outcome (mRS score 4-6) at 6 months (55% in both groups).
  • Adverse Events: Arrhythmias causing hemodynamic compromise were significantly more common in the hypothermia group than in the normothermia group (24% vs 17%; P<0.001).

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a Cox proportional-hazards model.
  • Primary Outcome Analysis: Time to death from any cause up to 6 months was compared between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death at 6 months: 1.04 (95% CI, 0.94 to 1.14; P=0.37).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk of death in hypothermia group) / (Risk of death in normothermia group).
      • Calculation: The paper reports the result as 1.04.
      • Clinical Meaning: An RR of 1.04 means there was a 4% higher relative risk of death in the hypothermia group compared to the normothermia group, but this was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.94 to 1.14.
      • Clinical Meaning: Since this narrow range is centered around the line of no effect (1.0), it provides a precise estimate that there is no significant difference between the two strategies. The true effect is likely somewhere between a 6% benefit and a 14% harm for hypothermia.
    • P-value:
      • Calculation: The reported p-value was 0.37.
      • Clinical Meaning: The p-value of 0.37 is well above the 0.05 threshold, meaning the observed small difference in mortality is very likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 48.2% – 50.3% = -2.1%. This is an absolute risk increase of 2.1%.
      • Clinical Meaning: The intervention was associated with a non-significant 2.1% absolute increase in the risk of death.
    • Number Needed to Treat (NNT): Not applicable, as the intervention showed no benefit and trended towards harm.
  • Subgroup Analyses: There was no benefit from hypothermia in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a very large, international, multicenter, randomized trial with blinded outcome assessment, providing a robust and definitive answer to the clinical question.
  • Generalizability: The pragmatic design and inclusion of 61 diverse ICUs make the findings highly generalizable.
  • Patient-Centered Outcomes: The primary outcome of 6-month mortality and the key secondary outcome of functional status are the most important endpoints for this patient population.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label for clinicians, which is a potential source of bias, though this is mitigated by the objective nature of the primary outcome and the blinded assessment of the secondary outcome.
  • External Validity (Generalizability): The findings apply to out-of-hospital cardiac arrest of presumed cardiac or unknown cause and may not be generalizable to in-hospital arrest or arrests from non-cardiac causes (e.g., asphyxia).
  • Other: The sedation protocols were standardized, which may not reflect the variability of real-world practice.

10. Conclusion of the Authors

“In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia at a temperature of 33°C did not lead to a lower incidence of death at 6 months than targeted normothermia.”

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial. It definitively demonstrated that inducing hypothermia to 33°C offers no benefit over a strategy of simply preventing fever in comatose survivors of out-of-hospital cardiac arrest. This has led to a major shift in international guidelines and clinical practice, moving away from routine active cooling and toward a focus on strict fever prevention (targeted normothermia).
  • Specific Recommendations:
    • Patient Selection: For adult patients who are comatose after an out-of-hospital cardiac arrest.
    • Actionable Intervention: The primary goal of temperature management should be the strict avoidance and treatment of fever (targeting a temperature ≤37.5-37.7°C).
    • Expected Benefit: No benefit from inducing hypothermia. A normothermia strategy avoids the increased risk of arrhythmias associated with cooling.
  • What This Trial Does NOT Mean: This trial does NOT mean that temperature management is unimportant. It strongly supports the active prevention of fever, which was the intervention in the control group. It is not a trial of “no temperature control” versus hypothermia.
  • Implementation Caveats: Strict fever control is an active process and may still require the use of cooling devices in many patients.

12. Context and Related Studies

  • Building on Previous Evidence: The TTM2 trial was the definitive successor to the HACA (2002) and Bernard (2002) trials, which first suggested a benefit for hypothermia, and the TTM trial (2013), which showed no difference between 33°C and 36°C. TTM2 was designed to answer the final question: is any level of cooling better than just preventing fever?
  • Influence on Subsequent Research: This trial has largely settled the question of therapeutic hypothermia in this population. Future research is now focused on other aspects of post-cardiac arrest care, such as blood pressure targets, oxygenation, and neuroprognostication.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Is there a benefit to hypothermia in other types of cardiac arrest, such as in-hospital arrest or arrests due to asphyxia?
  • Future Directions: The focus of post-cardiac arrest care research has shifted to optimizing other physiological parameters and improving the accuracy of neurological prognostication.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance, directly challenging a long-standing and resource-intensive standard of care.
  • Methods: The large, international RCT design was methodologically superb and provided a very high level of evidence. The use of a strong, active control group (fever prevention) was a key strength.
  • Results: The trial had a clear and robustly neutral result for its primary and secondary outcomes. The finding of increased harm (arrhythmias) in the hypothermia group further strengthens the conclusion.
  • Conclusions and Applicability: The authors’ conclusion is a direct and definitive interpretation of the data. The results are highly applicable to global critical care practice and have provided a clear, evidence-based directive to change the standard of care from therapeutic hypothermia to targeted normothermia.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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